Objective—Microvascular endothelium is one of the main targets of the inflammatory response. On specific activation,
endothelial cells recruit Th1-lymphocytes at the inflammatory site. We investigated the intracellular signaling mediating
tumor necrosis factor (TNF)- and interferon (IFN)- inflammatory response in human microvascular endothelial cells
(HMEC-1) and the interfering effects of the peroxisome-proliferator-activated-receptor (PPAR) agonist, rosiglitazone
(RGZ).
Methods and Results—TNF and IFN, mainly when combined, stimulate IFN-inducible protein of 10 kDa (IP10) and
fractalkine production evaluated by ELISA and TaqMan analyses. This effect is not only mediated by activation of the
NFkB and Stat1 classic pathways, but also involves a rapid increase in phosphorylation and activation of extracellular
signal-regulated kinases (ERK1/2) as measured by Western blot. RGZ interferes with TNF and IFN stimulation of
IP10, fractalkine, and adhesion molecule through a novel rapid mechanism which involves the blocking of ERK
activation.
Conclusions—Our findings shed new light on the mechanisms underlying the inflammatory response of microvascular
endothelium and on the possible therapeutic use of RGZ in vasculopathies involving Th1-responses. (Arterioscler
Thromb Vasc Biol. 2008;28:718-724)

Objective—Microvascular endothelium is one of the main targets of the inflammatory response. On specific activation,
endothelial cells recruit Th1-lymphocytes at the inflammatory site. We investigated the intracellular signaling mediating
tumor necrosis factor (TNF)- and interferon (IFN)- inflammatory response in human microvascular endothelial cells
(HMEC-1) and the interfering effects of the peroxisome-proliferator-activated-receptor (PPAR) agonist, rosiglitazone
(RGZ).
Methods and Results—TNF and IFN, mainly when combined, stimulate IFN-inducible protein of 10 kDa (IP10) and
fractalkine production evaluated by ELISA and TaqMan analyses. This effect is not only mediated by activation of the
NFkB and Stat1 classic pathways, but also involves a rapid increase in phosphorylation and activation of extracellular
signal-regulated kinases (ERK1/2) as measured by Western blot. RGZ interferes with TNF and IFN stimulation of
IP10, fractalkine, and adhesion molecule through a novel rapid mechanism which involves the blocking of ERK
activation.
Conclusions—Our findings shed new light on the mechanisms underlying the inflammatory response of microvascular
endothelium and on the possible therapeutic use of RGZ in vasculopathies involving Th1-responses. (Arterioscler
Thromb Vasc Biol. 2008;28:718-724)